Diabetes holds a 2-6 fold increased risk for acute ischemic stroke. Elevations in blood glucose due to preexisting diabetes or acute stress response is associated with higher incidence and severity of cerebral infarction, edema formation and the risk of hemorrhagic transformation (HT) that develops secondary to AIS complicating the stroke outcome. While most studies have focused on metabolic abnormalities and neuronal damage following I/R, targets to protect the vasculature from ischemic injury in the presence of preexisting diabetic vascular disease are unknown. In contrast to increased infract size in acute hyperglycemic stroke, we showed smaller infarct but greater HT following I/R in Goto-Kakizaki (GK) rats, a model of Type 2 diabetes. Global hypothesis is that impact of acute hyperglycemia vs. diabetes on the neurovascular unit and the mechanisms by which either exacerbates I/R injury are different. Three aims will test the subhypotheses that: 1) Diabetes, not acute hyperglycemia, induces neovascularization and matrix metalloproteinase (MMP)-dependent cerebrovascular remodeling, 2) Increased cerebrovascular tone limits perfusion resulting in stimulation of neuronal survival pathways which then contributes to smaller infarct size in diabetes, and 3) Diabetes-induced changes in vascular structure and tone promotes greater HT and smaller infarct whereas acute hyperglycemia causes greater infarct. At completion, we expect to have generated new and important data related to mechanisms of cerebrovascular damage in diabetes and acute hyperglycemia, which will enable us to develop neurovascular protection strategies in these high risk patients. Potential Impact on Veterans Health Care: We are well poised to conduct these studies since we have established collaborations with VA scientists that have provided support for the goals of this proposal. Since a high percentage of veterans suffer from diabetes, this project is highly relevant to the mission of Veterans Administration. Identification of causal factors and molecular mechanisms responsible for disruption of vascular integrity in diabetes will advance disease treatment by retarding the progression, delaying the onset, or even possibly preventing cerebrovascular disease and stroke in diabetes PUBLIC HEALTH RELEVANCE: Project Narrative: Most stroke patients present with elevated glucose levels even if they do not have diabetes. These patients have severe stroke outcomes. This project will determine the mechanisms of vascular protection before and after stroke under diabetic or acutely hyperglycemic conditions to develop treatment strategies in these high risk patients. Since a high percentage of veterans suffer from diabetes, this project is highly relevant to the mission of Veterans Administration.